: Ten neurodegenerative diseases (Huntington's disease; spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, 8 and 12; dentatorubral-pallidoluysian atrophy; and spinal and bulbar muscular atrophy) are now known to be caused by expansions of CAG/CTG trinucleotide repeats. The P.I. hypothesizes that similar disorders, including other forms of spinocerebellar ataxia, familial spastic paraplegia, and some types of familial Parkinsonism, may also be caused by expansions of CAG/CTG repeats. He proposes a three-part plan to test this hypothesis. First, the P.I. will search the genomes of subjects with progressive neurodegenerative disorders of unknown etiology with an assay (known as repeat expansion detection, or RED) that enables identification of long CAG/CTG repeat expansions. Expansions detected by this method will be cloned, along with flanking sequence, and they will develop PCR-based assays to search for the expansions in other subjects. Secondly, they will develop a catalogue of CAG/CTG repeats in the human genome. This will be accomplished by systematic searches of the genetic data banks, supplemented by cloning efforts in the P.I.'s laboratory in collaboration with Life Technologies, Inc. They will determine the reading frame (if any) of each repeat, localize each repeat to a chromosomal locus, develop a PCR assay for testing the length of each repeat, and place this information on a publicly accessible Web site. The P.I. and an extensive group of collaborators will use these assays to test for expansions of specific repeats in subjects and controls. Third, the P.I. will undertake preliminary mechanistic studies of novel expansion mutations, including determination of whether the expansion is transcribed and translated and the effect of the expansion on gene expression. Overall, the proposed experiments will enable a systematic test for CAG/CTG expansion mutations in a variety of devastating neurodegenerative diseases.